breast cabcer pom questions Flashcards
Is this woman likely to have inherited a genetic predisposition to cancer?
Indicators of familial cancer include involvement of close relatives, presence of cancer across successive generations (especially the same type of cancer), and early age of onset (for that type of cancer). Ovarian and breast cancers are more likely to occur after menopause, so the fact that this woman is presenting with breast cancer at 30 years old and has family history strongly suggests there is a heritable component.
Briefly explain the process of next generation sequencing.
Next generation sequencing allows multiple parts of the genome to be sequenced simultaneously which allows a more cost and time efficient method of identifying mutations. It involves taking DNA from a cell, breaking this into fragments then placing these fragments onto a microscope slide. Copies of these fragments will then be synthesised with polymerase enzymes, but the nucleotides that these copies are made out of are modified to each be labelled with a different coloured fluorescent marker (depending on which of the 4 nucleotides it is). As the polymerase enzymes add these nucleotides, there will be a visible flash of colour which can be identified under a microscopic video camera to sequence the order in which these flashes occur and therefore determine the order of nucleotides in the gene.
Why is it important to sequence her blood cells as well as the breast tumour cells?
Just analysing her tumour cells for mutations will not determine if the mutation is inherited or acquired. Sequencing her blood cells as well will show if the mutation is present in non-cancerous cells, which indicates it is a heritable germline mutation (such as a BRCA 1/2) which she could thene pass on to her children. Furthermore, sequencing her germline through her blood cells could also be beneficial in terms of identifying variations of genes that could impact how her body responds to certain medications (pharmacogenetics) that can then be used to guide treatment.
What is a tumour suppressor gene and why would it be relevant here?
A tumour suppressor gene is a gene that inhibits cell proliferation and tumour development. An example of heritable tumour suppressor gene mutations in breast cancer are BRCA1/2. As her family history is suggestive of heritable cancer, it is likely that this genetic mutation may be playing a role in the development of her cancer, as a mutated gene would result in uncontrolled cell division and growth.
Why is it important to determine the mutation present in this woman that is causing her cancer?
Determining the mutation present may reveal if there is a targetable gene that will respond to specific therapies. For example, genetic testing could reveal if she had increased expression of the Her2 gene then she could be treated with trastuzumab which is an artificially produced antibody that targets the Her2 receptor (EGFR) on epithelial cells. These antibodies degrade the receptor (which prevents the binding of ligands which ultimately result in cell proliferation through activating cell signalling pathways), but can also be recognised by the immune system as foreign and lead to killing of the tumour cells by CD8 T cells. However, trastuzumab is only effective if there is amplification of the Her2 gene - if this amplification is not present then it should not be given to patients due to the likelihood of cardiac side effects.
What is the importance of a high grade tumour?
Grade is a measurement of how unlike the original cell type the tumour cells are in terms of increased proliferation and decreased differentiation (anaplasia). Having a high grade tumour means there will be a significantly increased rate of mitotic division leading to rapid cell proliferation due to the fact that the signalling pathways that usually prevent uncontrolled cell growth are no longer working. Similarly, the signalling pathways that control cell differentiation will also no longer be working leading the cells to lack specialisation and potentially resemble embryonic stem cells. The reason that these signalling pathways are not working as they should be will be due to genetic mutations (such as single point mutations that convert a proto oncogene to an oncogene) or epigenetic changes (such as methylation of a tumour suppressor gene that causes it to become inactive).
Describe the difference between a benign and malignant tumour.
Benign tumours lack the ability to spread, and are confined to the site where they originally developed. Benign tumours are not classified as cancerous, although some benign tumours can become malignant due to further mutations. Malignant tumours have the ability to spread beyond the original site of development, which is the defining feature of cancer. Malignant tumours may not have yet spread from the primary site, but they have the potential to invade local lymph nodes or metastasise to distant locations through lymphatic spread or haematogenous spread.
What are some likely histological features seen in the biopsy of her breast tissue lump?
Pleomorphism (variation in size and shape between cells), hyperchromatic nuclei (stain more deeply than normal), increase in nucleus:cytoplasm ratio, loss of tissue architecture
What is the importance of high mutational burden for breast cancer?
Mutational burden represents the number of mutations in the coding region of a tumour, a proportion of which can be presented to the immune system as neoantigens. In breast cancer, having a higher mutational burden and therefore increased ability for the immune system to recognise tumour cells leads to a favourable prognosis and likely increased survival due to the fact that the immune system will be able to more effectively recognise and kill these tumour cells. It is important for there to be a range of different mutations (that produce presentable neoantigens) within a tumour because even if some tumour cells develop the ability to evade the immune system there will still be other cells that can be identified and killed.
What is the importance of malignant tumour cells being identified in her lymph node?
The presence of malignant tumour cells in her lymph node shows that the tumour cells have developed the ability to leave the primary site of origin to spread throughout the body, and may imply that there could be sites of secondary metastasis in distant organs.
Summarise the process of metastasis of tumour cells.
The initial tumour cells have to acquire invasive potential for them to be able to move away from the site of origin. This involves changing their characteristics, such as undergoing the epithelial to mesenchymal transition which enables them to mobilise and survive on their own (e.g. by secreting ECM then putting out projections that enables the cells to crawl along this ECM). They then must degrade through the basement membrane which may require increased protease activity and decreasing the integrity of their cell-cell adhesions. The tumour cells then must induce angiogenesis (of blood vessels or lymphatics) by secreting proangiogenic factors. Once these new capillaries are formed, the tumour can break off as single cells or clumps and intravasate into these vessels. Once in the vessels, they need to coat themselves with platelets or fibrin to evade the immune system, and also be able to cope with the increased oxygen exposure without dying. Once these cells travel to a site that is ideal for development of metastasis, they send signals that cause endothelial cells to become sticky and allow extravasation of the tumour cells into the tissue. If the environment in this secondary location is favourable for their growth they may immediately form a metastatic lesion but if not they may lie dormant until the environment changes.
- What is the relevance of the woman’s ethnicity in this case?
Women of Māori ethnicity with breast cancer have a higher risk of excess mortality.
Breast cancer incidence in Māori is lower in comparison to other ethnicities, and yet mortality rates are higher. A strong indication that there are equity issues that need to be addressed in cancer care
- Genomic testing has revealed a mutation in the BRCA1 gene. Discuss if a mutation is likely to be found in one or both alleles in this patient.
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BRCA1 is a tumour suppressor gene, so typically both alleles need to have a mutation for a cancerous phenotype to be expressed.
